Hepatic steatosis: A benign disease or a silent killer

Abstract

Steatosis is a coarse feature of many liver diseases, namely non-alcoholic steatohepatitis ( NASH ) and hepatitis C virus ( HCV ) infection, but the infective mechanisms differ. Insulin resistance ( IR ), a identify feature of metabolic syndrome, is all-important for NASH development, associated with many underlying genetically determined or acquired mitochondrial and metabolic defects and culminates to inflammation and progression to fibrosis. This may have likely implications for modern drug therapy. In HCV-related disease, steatosis impacts both fibrosis progress and response to treatment. Steatosis in HCV-related disease relates to both viral factors ( HCV genotype 3 ), and host factors ( alcohol consumption, fleshy, lipemia, diabetes ). Among others, IR is a accredit factor. hepatic steatosis is reported to be associated with disturbance in the signaling cascade of interferon and downregulation of its receptors. frankincense, liverwort steatosis should not be considered a benign feature, but rather a silent killer. Keywords:

Metabolic steatosis, Hepatitis C virus steatosis, Insulin resistance, Fibrosis progression

INTRODUCTION

Both hepatitis C contagion and non-alcoholic fatso liver disease ( NAFLD ) are major causes of liver related unwholesomeness and mortality. Hepatitis C virus ( HCV ) is a major cause of chronic liver disease with about 170 million people infect global. The severity of disease varies widely from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma ( HCC ) [ 1 ]. NAFLD represents a spectrum of liver diseases characterized chiefly by macrovesicular steatosis that occurs in the absence of alcoholic consumption. The hepatic histology varies from isolated hepatic steatosis alone “ first hit ” to fatty liver accompanied by hepatocellular damage plus inflammation known as steatohepatitis “ second hit ” which is followed by the development of fibrosis. Adipose tissue is now recognized as not plainly a memory storehouse for excess energy, but rather an active hormone harmonium that secretes a number of molecules termed, adipocytokines. A number of these adipocytokines have been linked to alterations in insulin sensitivity, including adiponectin, leptin, resistin, and tumor necrosis factor-α ( TNF-α ) [ 2, 3 ]. Insulin resistance ( IR ) is a major infective feature leading to liverwort fatty collection. In the interim, hepatitis C infection promotes IR. Two types of IR are found in chronic hepatitis C patients : “ viral ” and “ metabolic ” IR. IR in chronic hepatitis C is relevant because it promotes steatosis and fibrosis [ 4 ]. Metabolic IR is thought to be triggered by hepatic FFA accretion that may exacerbate overall IR [ 5 ] .

METABOLIC SYNDROME

metabolic Syndrome ( X-syndrome ) is a cluster of disorders including central fleshiness, IR with or without type 2 DM, dyslipidemia and high blood pressure. holocene findings linking the components of the metabolic syndrome with NAFLD and the progress to non-alcoholic steatohepatitis ( NASH ), fibrosis and cirrhosis will be reviewed. Metabolic syndrome was foremost described in 1988 by Reaven GM [ 6 ]. Whether liverwort IR causes cellular wound and excitement in the liver-colored or is the result of both excitement and steatosis is distillery undisclosed [ 7 ]. liverwort steatosis is caused by imbalance between the delivery of fat in the liver and its subsequent secretion or metamorphosis. In other words, fat accumulates when the delivery of fatso acids to the liver, either from the circulation or by de novo synthesis within the liver, exceeds that capacity of the liver to metabolize the fatty by β-oxidation or secrete it as very low-density lipoproteins ( VLDL ). Derangements in any of these pathways alone or in combination causes fat to accumulate in the liver .

Delivery of fatty acids from peripheral stores to the liver

Triglycerides ( TAG ) are stored in adipose weave and released as FFAs into the circulation through the actions of lipoprotein lipase. FFAs released from peripheral stores are hydrophobic and are powerfully bound to circulating albumin. FFAs are transported by albumin to the liver where they can then be used as a stand-in for β-oxidation, stored as TAG, or exported as VLDL. Excess glucose is converted to the liver, the backbone of most amino acids, can be converted to pyruvate and then to acetyl-coenzyme A ( acetyl-CoA ), which feeds immediately into cytosolic fatty acerb deduction. Processes that can lead to excessive FFAs delivery or impaired β-oxidation or secretion can lead to liverwort steatosis, increased mitochondrial reactive oxygen species ( ROS ) and lipid peroxidation products [ 8, 9 ] .

Fate of fatty acids in the liver

In the fast state, adipocyte TAG is hydrolyzed to release FFAs, which are transported to the liver-colored where they can serve as substrates for mitochondrial β-oxidation. β-oxidation of fatso acids is a major source of energy needed to maintain liver-colored viability during fasting. It is besides the beginning of the ketone bodies, acetoacetate and acetone. These are released into the rake and are essential fuel sources for peripheral tissues, when glucose is in unretentive supply. Defects in hepatic β-oxidation cause microvesicular steatosis of the liver, increase in oxidative stress due to extramitochondrial oxidative stress. ROS and peroxidation products lead to cytotoxic events, passing of proinflammatory cytokines and energizing of liverwort radial cells and fibrosis [ 8, 9 ] .

Formation and secretion of VLDL

In the feed submit, β-oxidation of fatty acids is not required as an energy generator, and fatso acids delivered to the liver are chiefly converted to TAG. Insulin regulates the metabolic path that fatty acids take in the liver-colored. Without insulin, creatinine palmitoyl transferase-I ( CPTI ) commit fatty acids to mitochondrial β-oxidation ; when insulin levels are high, glycerol-3-phosphate acetyltransferase commits fatty acids to the formation of TAG. This bulk of acetyl CoA entering the citric acid cycle, results in manner of speaking of electrons to the respiratory chain, where they generate ROS .

DEVELOPMENT OF STEATOHEPATITIS

Steatosis per southeast does not always lead to hepatocellular injury suggesting that a two-step model involving extra secondary insults is required for the incendiary part of steatohepatitis “ second hit ” [ 10 ]. Factors that lead to progressive liver injury are multifactorial and may include increase lipid peroxidation, FA toxicity, mitochondrial impairment, cytokine mediated hepatotoxicity, and oxidative injury. Hyperinsulinemia in the insulin-resistant country leads to increased FA oxidation promoting the development of ROS and oxidative injury [ 11 – 13 ]. Although there are no authentic human data supporting a causal function of oxidative injury in human NASH, animal data have suggested a likely function for oxidative injury [ 14 – 16 ]. excess fat in the liver predisposes to hepatocellular injury. This may be caused by direct cellular cytotoxicity of excess FFAs, oxidative tension, lipid peroxidation or other mechanisms. In the interim, IR may contribute to liverwort fatness accretion and plays a samara function in the development of steatohepatitis and disease progress [ 4 ]. furthermore, TNF-α secreted by the macrophages of the adipose weave which directly impairs insulin signal and is all-important for the passage of steatosis to steatohepatitis [ 17 ] through evocation of several proinflammatory cytokines. In addition, FFAs may lead to hepatocyte apoptosis which is one mechanism of cell injury in NAFLD [ 5 ]. Hepatocellular injury may cause incendiary reaction with subsequent cytokine induction, mitochondrial dysfunction and progressive fibrosis in a subset of patients [ 10 ]. In animal models, growth of steatohepatitis depends on extra factors, such as endotoxin exposure, acute liver injury ( for model, ischemia-reperfusion ), alcohol, excess dietary polyunsaturated fatty acids, or aging. A unite guess envisages that all causes capable of changing the oxidation-reduction equilibrium of the hepatocyte may result in liver ignition and fibrogenesis activation. ROS may promote hepatic radial cell energizing and collagen fiber deposit [ 18 ]. Lipid peroxidation products may elicit activation of nuclear factors that lead to procollagen typeIoverexpression [ 19 ]. Some investigators have used a taxonomic eminence of secondary NASH, or that attributable to readily identifiable drugs, toxins, or familial abnormalities, and elementary NASH, which is probably related to IR [ 20 ] .

FIBROSIS PROGRESSION IN NASH

progression of fibrosis in NASH has been histologically demonstrated in 32 % -37 % of the patients [ 21, 22 ]. Estimated rates of cirrhosis exploitation over 10 years of 5 % -20 % have been reported by 3 independent studies [ 23 – 25 ]. NASH patients with advance fibrosis are at risk of developing liver complications [ 25 ]. Obesity, diabetes, IR and the initial austereness of the fibrosis are the factors most prominently associated with fibrotic progress [ 23 – 25 ]. The mechanism by which IR promotes fibrosis progression admit : steatosis, hyperleptinemia, increased TNF production, impair expression of PPAR-γ receptors [ 4 ]. hepatic injury in NASH induces oxidative stress, ROS and peroxidation products which lead to cytotoxic events, liberation of proinflammatory cytokines that activate hepatic radial cells and deposit of collagen [ 8, 9 ]. HCC has been detected in respective NASH patients, most often at the time of diagnosis, and rarely, during follow up [ 23, 26, 27 ]. In the larger Olmsted County Community Study [ 26 ], 2 of 420 NAFLD patients developed HCC during a 7-year follow-up period. The calculate pace of liver-related deaths over 10 years was 12 % for NASH patients [ 24, 25 ] .

ROLE OF HYPERTENSION

high blood pressure is one of the independent components of metabolic syndrome. The renin-angiotensin system ( RAS ) plays a role in progression of chronic liver disease to fibrosis, and HCC and this action is mediated via respective mechanisms such as direct effect on activated HSCs and neovascularization [ 28 ]. RAS is frequently activated in patients with chronic liver disease. In animal models, tell has shown that angiotensin 2 receptor adversary and angiotensin-converting enzyme ( ACE ) inhibitors display antifibrotic characteristics via the hepatic radial cellular telephone proliferation [ 29 ]. In a fly learn examining the therapeutic efficacy of angiotensin 2 receptor antagonist, losartan was studied in patients with NASH and high blood pressure. seven patients were treated with losartan ( 50 mg/d ) for 48 wk. After 48 wk, patients not only showed a significant decrease in lineage markers of liverwort fibrosis, but besides an improvement in serum transaminase levels [ 30 ]. however, recent evidence that angiotensin 2 sense organ antagonists and ACE inhibitors are antifibrotic in animal models of hepatic fibrosis suggests that these agents are worth examining in clinical trials [ 29 ]. high blood pressure should be sought and treated appropriately in patients with NAFLD, particularly those with type 2 DM in whom taut blood imperativeness control ( < 140/80 mmHg ) with an ACE inhibitor or a β-blocker significantly reduces the risk of cardiovascular unwholesomeness, sudden death, stroke and peripheral vascular disease [ 31, 32 ] .

BIOLOGICAL ROLE OF INSULIN

Insulin, after binding its receptor, induces the phosphorylation of receptor substrates in the liver and muscles, and triggers respective steps toward the transactivation of glucose transporter-4 ( GLUT-4 ) .This increases glucose consumption by cells and its storehouse as glycogen, and inhibits the web product of glucose by the liver, therefore blocking glycogenolysis and neoglycogenesis. furthermore, insulin promotes lipid storage by inhibiting lipolysis. When insulin is unable to induce glucose consumption, pancreatic β-cells increase insulin product and the hyperinsulinemic express prevents hyperglycemia. thus, IR depends on insulin secretion and insulin sensitivity .

IR

IR is defined as a condition in which higher-than-normal insulin concentrations are needed to achieve normal metabolic responses or, alternatively, normal insulin concentrations are ineffective to achieve normal metabolic responses [ 33 ]. Hyperinsulinemia appears as a consequence of the inability of insulin to induce its effect on glucose metamorphosis, and hence, an abnormally boastfully measure of insulin is secreted to achieve a biological response with attendant several abnormalities in aim organs such as the liver-colored, endothelium, and kidneys, and this represents the chief feature in the metabolic syndrome [ 4 ]. IR is measured by many ways. The most accurate is euglycemic-hyperinsulinemic clamp method acting whereas the less accurate, but widely applied, is Homeostasis Model Assessment ( HOMA ). Mean HOMA index increases with the phase of fibrosis and could help to differentiate stages of fibrosis [ 34 ] .

Pathogenesis of IR

pathogenesis of IR is not fully silent. IR is thought to be the key infective feature leading to liverwort fatty accretion. It causes an increase in FFA inflow into the liver that drives hepatic triglyceride production. Increased serum insulin and glucose levels besides promote de novo lipogenesis by upregulating lipogenic recording factors. NAFLD may in turn result in hepatic IR, which is thought to be triggered by liverwort FFA accumulation and their metabolites that may exacerbate overall IR [ 5 ].

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TNF-α is liberated by macrophage of adipose tissues of corpulent persons and worsens IR. Typically patients with NASH have besides low serum adiponectin which is considered a potent insulin foil [ 17 ] .

IR in hepatitis C

HCV immediately associates with IR independent of the visceral adipose tissue area in non-obese and non-diabetic patients [ 35 ]. The mechanism by which hepatitis C induces increased IR and the gamble for development of diabetes has not been completely understand. Liver fibrosis progression has been considered, for a long time, creditworthy for the appearance of IR and type 2 diabetes in patients with chronic liver diseases [ 4 ]. late data support a connection between HCV replication and IR, and HOMA decreased when the virus was eradicated. Besides, the incidence of diabetes type 2 is unlike in bring around patients than in non-responders, supporting a better control of IR after HCV clearance [ 36 ]. consequently, hepatitis C promotes IR and IR induces interferon electric resistance, steatosis and fibrosis progress in a genotype-dependent manner [ 4 ]. across-the-board evidence supports a cardinal function of TNF-α and other proinflammatory cytokines in the growth of obesity-associated IR and fatso liver [ 37 ]. HCV infection promotes IR, chiefly by increased TNF-α production together with enhancement of suppressor of cytokine ( SOC ) -3 ; both events block PI3K and Akt phosphorylation. Two types of IR can be found in chronic hepatitis C patients : “ viral ” and “ metabolic ” IR [ 4 ]. Both HCV and TNF-α downregulate IRS-1, 2 phosphorylation via upregulation of SOCS-3, which degrades the insulin receptor. Furthermore, HCV core protein per southeast, or its inflammatory cytokine ( TNF-α ), interfere with normal insulin signaling which impairs translocation of CLUT-4 transporters to plasma membrane limiting glucose consumption and increases blood glucose/insulin level leading to IR. In the entail fourth dimension, TNF-α impairs construction of PPAR-γ receptor which in turn, decreases insulin sensitivity [ 4 ] .

STEATOSIS IN CHRONIC HEPATITIS C

In chronic hepatitis C patients, the prevalence of steatosis ranges from 40 % to 86 % ( intend, 55 % ) [ 38, 39 ]. The majority of patients with steatosis ( 78 % ) have mild steatosis affecting less than 30 % of hepatocytes. frankincense, steatosis occurs more frequently in patients with chronic hepatitis C ( 55 % ) than in the general population ( 20 % -30 % ) of adults in the western worldly concern [ 40 ]. Macrovesicular steatosis is found in the periportal area of the liver-different from the centrilobular distribution characteristic of NASH patients. Mild steatosis had been reported in closely 40 % of patients with HCV genotype 4 [ 41 ]. Moderate or severe steatosis is significantly less frequent in genotype 4 than 3 chronic hepatitis C patients and alike between genotype 4 and 1. In non-diabetic, corpulence patients, mince or dangerous steatosis is award in only 10 % -15 % of genotype 4 or 1 compared with 40 % of genotype 3 patients. frankincense, liverwort steatosis in genotype 4 is largely associated with metabolic factors, alike to those in genotype 1 [ 41, 42 ]. It has been shown that HCV genotype 3 is associated with higher quasispecies heterogeneity than genotype 1 [ 43 ]. Serum levels of apolipoprotein B and cholesterol are reduced in patients in whom steatosis responds to antiviral therapy [ 44 ]. Hypocholesterolemia in patients with chronic hepatitis C ( specially genotype 3 ) has been reported by others [ 45, 46 ]. rather, after antiviral treatment, virus-related steatosis disappears whereas master of ceremonies associated steatosis remains unmoved [ 1 ]. Thus the disappearance of steatosis correlates with standardization of apolipoprotein B and cholesterol levels .

Pathogenesis of steatosis in chronic hepatitis C

IR emerges as a very important host factor, chiefly because it has been related to steatosis growth, fibrosis progression and non-response to peg-interferon asset ribavirin. HCV directly associates with IR independent of the intuitive fat area in non-obese and non-diabetic patients. HCV is directly associated with IR in a dose-dependent manner, independent of the visceral adipose tissue area [ 35 ]. Factors associated with steatosis in chronic hepatitis C are : ( 1 ) viral factor ( HCV genotype 3 ) ; ( 2 ) host factors ( alcohol consumption, fleshy, lipemia, diabetes, insulin resistance ), and ( 3 ) drug therapy ( corticosteroids, amiodarone, methotrexate, etc ) [ 1 ]. The mechanism underlying the development of parenchymal steatosis in HCV infection are not precisely known [ 47 ]. The beginning mechanism supposes that HCV core protein may block forum of Apo-A1-A2 with TAG. This will result in decrease export of TAG tie down to apolipoprotein-β ( Apo-β ) as VLDL out of hepatocyte, which is corrected by antiviral therapy [ 1 ]. Others propose that the core protein induces oxidative stress within the mitochondrion that contributes to lipid collection [ 48 ]. Though the accurate mechanism remains elusive, it seems that HCV itself can directly induce steatosis in genotype 3 [ 49 ] by the cytopathic effect of gamey titer of intracytoplasmic negative chain HCV RNA [ 39 ]. The second proposed mechanism recognizes IR as the major mechanism in the pathogenesis of hepatic steatosis [ 49 – 53 ]. It has been reported that IR plays a central character in NAFLD. however, the mechanisms of development of IR in patients with chronic HCV infection are not well understand [ 54, 55 ]. IR causes impair metabolic clearance of glucose, compensatory hyperinsulinemia, and increased lipolysis. The latter leads to increased plasma FFAs ; increased hepatic uptake of FFAs by the liver which results in steatosis [ 9 ]. furthermore, it has been suggested that IR may result from excess FFAs, TNF-α and suppressor of cytokine bespeak ( SOCS ) which could downregulate insulin receptor substrate ( IRS ) -1 signaling [ 20 ]. This will result in the impair translocation of GLUT-4 transporters to the plasma membrane which limits glucose consumption ; increases rake glucose and cause a compensatory increase in insulin [ 56 – 58 ]. recently, Pazienza et aluminum reported that both genotype 3a and 1b downregulates IRS-1 through genotype-specific mechanisms [ 59 ]. Furthermore, Fartoux L et alabama reported that IR depends chiefly on the age of the patient [ 34 ]. It has been suggested that old age associated decline in mitochondrial function could contribute to IR [ 34, 60 ]. The main deleterious effect of IR in chronic hepatitis C is the ability to promote fibrosis progress. high serum glucose levels have been found associated with an increase pace of fibrosis progress, even greater than corpulence [ 61 ] .

Steatosis and fibrosis progression in HCV

high levels of TNF-α have besides been observed in human chronic hepatitis C patients [ 40 ]. TNF-α has been shown to induce IR in experimental animals and civilized cells [ 62, 63 ]. prohibition of tyrosine phosphorylation of IRS 1 and 2 may be one of the mechanisms by which a high level of TNF-α causes IR [ 63 – 65 ]. Administration of an anti-TNF-α antibody restores insulin sensitivity [ 66 ]. These results provide mastermind experimental attest for the contribution of HCV in the exploitation of IR. There are experimental arguments for a conduct function of insulin in fibrosis progress in HCV infection [ 1 ]. epidemiologic studies indicating that the state of IR nowadays associated with NASH is besides associated with an increased risk of HCC. It is deserving mentioning that diabetes increases the risk of chronic liver disease and HCC [ 67 ] .

RESPONSE TO INTERFERON THERAPY IN HCV INFECTION

The current discussion for patients with chronic hepatitis C is the addition of ribavirin to interferon-based therapies for 24 to 48 wk. unfortunately, a nourish virological response ( SVR ) is achieved in alone 42 % -52 % of treatment-naive patients, and the rest either show no reply or experience a backsliding when therapy is stopped [ 68 ]. The mechanism underlying the failure of interferon therapy are not well understand, but testify indicates that in addition to viral factors, several host factors are besides involve [ 69 ]. Among master of ceremonies factors, IR has been found to impair virological response to combined therapy in chronic hepatitis C patients [ 70 ]. Hyperinsulinemia interferes with IFN signaling cascade [ 71 ] through upregulation of SOCS and energizing of phosphatidylinositol-3-kinase ( PI3K ) that inhibit phosphorylation of STAT1. In addition to IR, HCV congress of racial equality protein and TNF-α cytokine, derived chiefly from macrophages of adipose tissue, upregulate SOCS-3 which binds to Janus Kinase inhibiting phosphorylation of STAT1, finally interfering with interferon signaling [ 4 ]. SOCS-3 besides causes abasement of IRS-1, in turn leading further to interference with insulin signaling and hyperinsulinemia that interferes finally with interferon signaling [ 71 ]. holocene data support a connection between HCV replication and IR and HOMA decreased when the virus was eradicated [ 4 ]. HCV directly associates with IR freelancer of the visceral fat area in non-obese and non-diabetic patients [ 35 ]. In addition to IR, fleshiness and hepatic steatosis have been recognized as freelancer risk factors for a inadequate answer to IFN-α therapy [ 72, 73 ]. In corpulent individuals, hypodermic fat could cause a reduction in the initial absorption and bioavailability of interferon given subcutaneously [ 72 ]. In the interim, fleshiness and liverwort steatosis mar immune responses to HCV and increase fibrosis progression in corpulent patients [ 73 ]. furthermore, hyperleptinemia in corpulent is an mugwump risk factor for non-response to antiviral therapy [ 74 ]. Hyperferritinemia downregulates the reception to interferon therapy [ 75, 76 ]. From this review, we have noted that steatosis, either metabolic or cytopathic, contributes to the development of NASH and progression to fibrosis, cirrhosis and HCC. accordingly, we can conclude with assurance that liverwort steatosis is not a benign disease, but quite a mum killer .

Peer reviewers: Natalia A Osna, Liver Study Unit, Research Service ( 151 ), VA Medical Center, 4101 Woolworth Avenue, Omaha NE 68105, United States ; Mark J Czaja, MD, Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, United States ; Cintia Siqueira, PhD, Center of Gastroenterology, Institute of Molecular Medicine, Av. Prof. Egas Moniz, Lisboa 1649-028, Portugal

S- Editor Li DL L- Editor Rippe RA E- Editor Yin DH

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